PENCIL imaging: A novel approach for neuromelanin sensitive MRI in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is associated with the loss of neuromelanin (NM) and increased iron in the substantia nigra (SN). Magnetization transfer contrast (MTC) is widely used for NM visualization but has limitations in brain coverage and scan time. This study aimed to develop a new approach called Proton-density Enhanced Neuromelanin Contrast in Low flip angle gradient echo (PENCIL) imaging to visualize NM in the SN. METHODS: This study included 30 PD subjects and 50 healthy controls (HCs) scanned at 3T. PENCIL and MTC images were acquired. NM volume in the SN pars compacta (SNpc), normalized image contrast (Cnorm), and contrast-to-noise ratio (CNR) were calculated. The change of NM volume in the SNpc with age was analyzed using the HC data. A group analysis compared differences between PD subjects and HCs. Receiver operating characteristic (ROC) analysis and area under the curve (AUC) calculations were used to evaluate the diagnostic performance of NM volume and CNR in the SNpc. RESULTS: PENCIL provided similar visualization and structural information of NM compared to MTC. In HCs, PENCIL showed higher NM volume in the SNpc than MTC, but this difference was not observed in PD subjects. PENCIL had higher CNR, while MTC had higher Cnorm. Both methods revealed a similar pattern of NM volume in SNpc changes with age. There were no significant differences in AUCs between NM volume in SNpc measured by PENCIL and MTC. Both methods exhibited comparable diagnostic performance in this regard. CONCLUSIONS: PENCIL imaging provided improved CNR compared to MTC and showed similar diagnostic performance for differentiating PD subjects from HCs. The major advantage is PENCIL has rapid whole-brain coverage and, when using STAGE imaging, offers a one-stop quantitative assessment of tissue properties.

Neuromelanin-sensitive magnetic resonance imaging: Possibilities and promises as an imaging biomarker for Parkinson's disease.

Parkinson's disease (PD) is an age-related progressive neurodegenerative disorder characterized by both motor and non-motor symptoms resulting from the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and noradrenergic neurons in the locus coeruleus (LC). The current diagnosis of PD primarily relies on motor symptoms, often leading to diagnoses in advanced stages, where a significant portion of SNpc dopamine neurons has already succumbed. Therefore, the identification of imaging biomarkers for early-stage PD diagnosis and disease progression monitoring is imperative. Recent studies propose that neuromelanin-sensitive magnetic resonance imaging (NM-MRI) holds promise as an imaging biomarker. In this review, we summarize the latest findings concerning NM-MRI characteristics at various stages in patients with PD and those with atypical parkinsonism. In conclusion, alterations in neuromelanin within the LC are associated with non-motor symptoms and prove to be a reliable imaging biomarker in the prodromal phase of PD. Furthermore, NM-MRI demonstrates efficacy in differentiating progressive supranuclear palsy (PSP) from PD and multiple system atrophy with predominant parkinsonism. The spatial patterns of changes in the SNpc can be indicative of PD progression and aid in distinguishing between PSP and synucleinopathies. We recommend that patients with PD and individuals at risk for PD undergo regular NM-MRI examinations. This technology holds the potential for widespread use in PD diagnosis.

Increased iron in the substantia nigra pars compacta identifies patients with early Parkinson'sdisease: A 3T and 7T MRI study.

Degeneration in the substantia nigra (SN) pars compacta (SNc) underlies motor symptoms in Parkinson's disease (PD). Currently, there are no neuroimaging biomarkers that are sufficiently sensitive, specific, reproducible, and accessible for routine diagnosis or staging of PD. Although iron is essential for cellular processes, it also mediates neurodegeneration. MRI can localize and quantify brain iron using magnetic susceptibility, which could potentially provide biomarkers of PD. We measured iron in the SNc, SN pars reticulata (SNr), total SN, and ventral tegmental area (VTA), using quantitative susceptibility mapping (QSM) and R2* relaxometry, in PD patients and age-matched healthy controls (HCs). PD patients, diagnosed within five years of participation and HCs were scanned at 3T (22 PD and 23 HCs) and 7T (17 PD and 21 HCs) MRI. Midbrain nuclei were segmented using a probabilistic subcortical atlas. QSM and R2* values were measured in midbrain subregions. For each measure, groups were contrasted, with Age and Sex as covariates, and receiver operating characteristic (ROC) curve analyses were performed with repeated k-fold cross-validation to test the potential of our measures to classify PD patients and HCs. Statistical differences of area under the curves (AUCs) were compared using the Hanley-MacNeil method (QSM versus R2*; 3T versus 7T MRI). PD patients had higher QSM values in the SNc at both 3T (padj = 0.001) and 7T (padj = 0.01), but not in SNr, total SN, or VTA, at either field strength. No significant group differences were revealed using R2* in any midbrain region at 3T, though increased R2* values in SNc at 7T MRI were marginally significant in PDs compared to HCs (padj = 0.052). ROC curve analyses showed that SNc iron measured with QSM, distinguished early PD patients from HCs at the single-subject level with good diagnostic accuracy, using 3T (mean AUC = 0.83, 95 % CI = 0.82-0.84) and 7T (mean AUC = 0.80, 95 % CI = 0.79-0.81) MRI. Mean AUCs reported here are from averages of tests in the hold-out fold of cross-validated samples. The Hanley-MacNeil method demonstrated that QSM outperforms R2* in discriminating PD patients from HCs at 3T, but not 7T. There were no significant differences between 3T and 7T in diagnostic accuracy of QSM values in SNc. This study highlights the importance of segmenting midbrain subregions, performed here using a standardized atlas, and demonstrates high accuracy of SNc iron measured with QSM at 3T MRI in identifying early PD patients. QSM measures of SNc show potential for inclusion in neuroimaging diagnostic biomarkers of early PD. An MRI diagnostic biomarker of PD would represent a significant clinical advance.

Dopamine neuron activity encodes the length of upcoming contralateral movement sequences.

Dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNc) have been related to movement speed, and loss of these neurons leads to bradykinesia in Parkinson's disease (PD). However, other aspects of movement vigor are also affected in PD; for example, movement sequences are typically shorter. However, the relationship between the activity of DANs and the length of movement sequences is unknown. We imaged activity of SNc DANs in mice trained in a freely moving operant task, which relies on individual forelimb sequences. We uncovered a similar proportion of SNc DANs increasing their activity before either ipsilateral or contralateral sequences. However, the magnitude of this activity was higher for contralateral actions and was related to contralateral but not ipsilateral sequence length. In contrast, the activity of reward-modulated DANs, largely distinct from those modulated by movement, was not lateralized. Finally, unilateral dopamine depletion impaired contralateral, but not ipsilateral, sequence length. These results indicate that movement-initiation DANs encode more than a general motivation signal and invigorate aspects of contralateral movements.

Therapeutic Effects of Selenium on Alpha-Synuclein Accumulation in Substantia Nigra Pars Compacta in a Rat Model of Parkinson's Disease: Behavioral and Biochemical Outcomes.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder characterized by the accumulation of accumulated alpha-synuclein (α-Syn) in substantia nigra. Research has shown that selenium (Se) can protect neural cells through the actions of selenoproteins, including selenoprotein P (SelP) and selenoprotein S (SelS), which participate in endoplasmic reticulum-associated protein degradation (ERAD). In this study, we investigated the potential protective role of Se in a pre-clinical PD rat model.We aimed to evaluate the therapeutic effects of Se administration in the 6-hydroxydopamine (6-OHDA) induced unilateral rat PD model. Male Wistar rats were utilised for unilateral PD animal model which were subjected to stereotaxic surgery and injected with 20 µg 6-OHDA/5 µl 0.2% ascorbate saline. After confirming the model, the rats were intraperitoneally injected with 0.1, 0.2, and 0.3 mg/kg of sodium selenite for 7 days. We then performed behavioral tests, including apomorphine-induced rotation, hanging, and rotarod tests. Following sacrifice, we analysed the substantia nigra area of the brain and serum for protein quantification, element analysis, and gene expression analysis.Our results indicate that the administration of 0.3 mg/kg of Se improved the motor deficiency in hanging, rotarod, and apomorphine-induced rotational tests. While there was no significant improvement in the expression of α-Syn, Se increased the expression of selenoproteins. Additionally, levels of selenoproteins, Se, and α-Syn both brain and serum were re-established by the treatment, suggesting the role of Se on the α-Syn accumulation. Furthermore, Se improved PD-induced biochemical deficits by increasing the levels of SelS and SelP (p<0.005).In conclusion, our findings suggest that Se may have a protective role in PD. 0.3 mg/kg dosage of Se increased the expression of selenoproteins, reduced the accumulation of α-Syn in the brain, and improved PD-induced motor deficits. These results suggest that Se may be a potential therapeutic option for PD treatment.

Optogenetic action potentials and intrinsic pacemaker interplay in retrogradely identified midbrain dopamine neurons.

Dissecting the diversity of midbrain dopamine (DA) neurons by optotagging is a promising addition to better identify their functional properties and contribution to motivated behavior. Retrograde molecular targeting of DA neurons with specific axonal projection allows further refinement of this approach. Here, we focus on adult mouse DA neurons in the substantia nigra pars compacta (SNc) projecting to dorsal striatum (DS) by demonstrating the selectivity of a floxed AAV9-based retrograde channelrhodopsin-eYFP (ChR-eYFP) labeling approach in DAT-cre mice. Furthermore, we show the utility of a sparse labeling version for anatomical single-cell reconstruction and demonstrate that ChR-eYFR expressing DA neurons retain intrinsic functional properties indistinguishable from conventionally retrogradely red-beads-labeled neurons. We systematically explore the properties of optogenetically evoked action potentials (oAPs) and their interaction with intrinsic pacemaking in this defined subpopulation of DA neurons. We found that the shape of the oAP and its first derivative, as a proxy for extracellularly recorded APs, is highly distinct from spontaneous APs (sAPs) of the same neurons and systematically varies across the pacemaker duty cycle. The timing of the oAP also affects the backbone oscillator of the intrinsic pacemaker by introducing transient "compensatory pauses". Characterizing this systematic interplay between oAPs and sAPs in defined DA neurons will also facilitate a refinement of DA neuron optotagging in vivo.

The effect of SARS-CoV-2 on the development of Parkinson's disease: the role of α-synuclein.

The current coronavirus disease 2019 (COVID-19) can lead to various neurological complications in infected people. These neurological effects include problems in both central nervous system (CNS) and peripheral nervous system (PNS). Hyposmia, a PNS symptom of COVID-19, frequently manifests in the early stages of Parkinson's disease (PD) and serves as an early warning sign of the condition. In addition, the olfactory system is recognized as an early site for the onset of α-synuclein pathology, the pathological hallmark of PD. PD is characterized by accumulation and aggregation of misfolded α-synuclein (α-Syn) into Lewy bodies and Lewy neurites, resulting in the degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Previous research has also shown the involvement of α-Syn in the innate immune response following viral infections. Consequently, the potential link between viral infections and development of PD has gained attention in recent years. However, it's still too early to definitively conclude whether COVID-19 can cause Parkinsonism. Nevertheless, we can explore the likelihood of this connection by examining past studies and possible mechanisms to better understand how COVID-19 might potentially lead to PD following the infection. Based on the various pieces of evidence discussed in this review, we can infer that SARS-CoV-2 promotes the aggregation of α-Syn and, ultimately, leads to PD through at least two mechanisms: the stable binding of the S1 protein to proteins prone to aggregation like α-Syn, and the upregulation of α-Syn as part of the immune response to the infection.

A genetic and transcriptomic assessment of the KTN1 gene in Parkinson's disease risk.

Parkinson's disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. An association has been described between KTN1 genetic variants and changes in its expression in the putamen and substantia nigra brain regions and an increased risk for PD. Here, we examine the link between PD susceptibility and KTN1 using individual-level genotyping data and summary statistics from the most recent genome-wide association studies (GWAS) for PD risk and age at onset from the International Parkinson's Disease Genomics Consortium (IPDGC), as well as whole-genome sequencing data from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative. To investigate the potential effect of changes in KTN1 expression on PD compared to unaffected individuals, we further assess publicly available expression quantitative trait loci (eQTL) results from GTEx v8 and BRAINEAC and transcriptomics data from AMP-PD. Overall, we found no genetic associations between KTN1 and PD in our cohorts but found potential evidence of differences in mRNA expression, which needs to be further explored.

Distribution, connection and function of ALDH1A1+/TH+ neurons in substantia nigra pars reticulata of mouse.

The massive cell death of dopaminergic neurons (DANs) in substantia nigra pars compacta (SNC) is associated with motor diseases, such as Parkinson's disease. Moreover, as a subtype of DANs in SNC, ALDH1A1+ neurons show better resistance to PD related neurotoxin. DANs can also be found in the substantia nigra pars reticulata (SNR), however, whether they are ALDH1A1+ neurons are rarely reported, as well as their projection, function, and reaction in the PD pathology. We studied the distribution of ALDH1A1+ neurons and track their projection by injecting pAAV. We figured out that, in SNR, 87 % neurons are ALDH1A1+/TH+ in ALDH1A1+ cluster averagely, while ALDH1A1+/TH+: TH+ is 52 % averagely. There are two enrichment regions of ALDH1A1+/TH+ neurons at brgma -3.40 mm and brgma -3.70 mm in the SNR of the nTg mice. Nevertheless, in one type of PD-liked mice model, the proportion of ALDH1A1+/TH+: ALDH1A1+ neurons are 98 % averagely, while ALHD1A1+/TH+: TH+ is 57 %. Intriguingly, neuro-tracing discovered that there may be a previously unreported connection between SNR and anterior dorsal thalamus (ADT). The mouse received MPTP stereotactic injection to destroy TH+ neurons in SNR showed depression behavior, indicated the DANs death in SNR may contribute to depression behavior.

Mitochondrial homeostasis regulation: A promising therapeutic target for Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of Lewy bodies (LBs) or Lewy neurites (LNs) which consist of α-synuclein (α-syn) and a complex mix of other biomolecules. Mitochondrial dysfunction is widely believed to play an essential role in the pathogenesis of PD and other related neurodegenerative diseases. But mitochondrial dysfunction is subject to complex genetic regulation. There is increasing evidence that PD-related genes directly or indirectly affect mitochondrial integrity. Therefore, targeted regulation of mitochondrial function has great clinical application prospects in the treatment of PD. However, lots of PD drugs targeting mitochondria have been developed but their clinical therapeutic effects are not ideal. This review aims to reveal the role of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases based on the mitochondrial structure and function, which may highlight potential interventions and therapeutic targets for the development of PD drugs to recover mitochondrial dysfunction in neurodegenerative diseases.

Reduction in the activity of VTA/SNc dopaminergic neurons underlies aging-related decline in novelty seeking.

Curiosity, or novelty seeking, is a fundamental mechanism motivating animals to explore and exploit environments to improve survival, and is also positively associated with cognitive, intrapersonal and interpersonal well-being in humans. However, curiosity declines as humans age, and the decline even positively predicts the extent of cognitive decline in Alzheimer's disease patients. Therefore, determining the underlying mechanism, which is currently unknown, is an urgent task for the present aging society that is growing at an unprecedented rate. This study finds that seeking behaviors for both social and inanimate novelties are compromised in aged mice, suggesting that the aging-related decline in curiosity and novelty-seeking is a biological process. This study further identifies an aging-related reduction in the activity (manifesting as a reduction in spontaneous firing) of dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Finally, this study establishes that this reduction in activity causally underlies the aging-related decline in novelty-seeking behaviors. This study potentially provides an interventional strategy for maintaining high curiosity in the aged population, i.e., compensating for the reduced activity of VTA/SNc dopaminergic neurons, enabling the aged population to cope more smoothly with the present growing aging society, physically, cognitively and socioeconomically.

Behavioral, neural and ultrastructural alterations in a graded-dose 6-OHDA mouse model of early-stage Parkinson's disease.

Studying animal models furthers our understanding of Parkinson's disease (PD) pathophysiology by providing tools to investigate detailed molecular, cellular and circuit functions. Different versions of the neurotoxin-based 6-hydroxydopamine (6-OHDA) model of PD have been widely used in rats. However, these models typically assess the result of extensive and definitive dopaminergic lesions that reflect a late stage of PD, leading to a paucity of studies and a consequential gap of knowledge regarding initial stages, in which early interventions would be possible. Additionally, the better availability of genetic tools increasingly shifts the focus of research from rats to mice, but few mouse PD models are available yet. To address these, we characterize here the behavioral, neuronal and ultrastructural features of a graded-dose unilateral, single-injection, striatal 6-OHDA model in mice, focusing on early-stage changes within the first two weeks of lesion induction. We observed early onset, dose-dependent impairments of overall locomotion without substantial deterioration of motor coordination. In accordance, histological evaluation demonstrated a partial, dose-dependent loss of dopaminergic neurons of substantia nigra pars compacta (SNc). Furthermore, electron microscopic analysis revealed degenerative ultrastructural changes in SNc dopaminergic neurons. Our results show that mild ultrastructural and cellular degradation of dopaminergic neurons of the SNc can lead to certain motor deficits shortly after unilateral striatal lesions, suggesting that a unilateral dose-dependent intrastriatal 6-OHDA lesion protocol can serve as a successful model of the early stages of Parkinson's disease in mice.

Repeated Methamphetamine Administration Results in Axon Loss Prior to Somatic Loss of Substantia Nigra Pars Compacta and Locus Coeruleus Neurons in Male but Not Female Mice.

Methamphetamine (meth) is a neurotoxic psychostimulant that increases monoamine oxidase (MAO)-dependent mitochondrial oxidant stress in axonal but not somatic compartments of substantia nigra pars compacta (SNc) and locus coeruleus (LC) neurons. Chronic meth administration results in the degeneration of SNc and LC neurons in male mice, and MAO inhibition is neuroprotective, suggesting that the deleterious effects of chronic meth begin in axons before advancing to the soma of SNc and LC neurons. To test this hypothesis, mice were administered meth (5 mg/kg) for 14, 21, or 28 days, and SNc and LC axonal lengths and numbers of neurons were quantified. In male mice, the SNc and LC axon lengths decreased with 14, 21, and 28 days of meth, whereas somatic loss was only observed after 28 days of meth; MAO inhibition (phenelzine; 20 mg/kg) prevented axonal and somatic loss of SNc and LC neurons. In contrast, chronic (28-day) meth had no effect on the axon length or numbers of SNc or LC neurons in female mice. The results demonstrate that repeated exposure to meth produces SNc and LC axonal deficits prior to somatic loss in male subjects, consistent with a dying-back pattern of degeneration, whereas female mice are resistant to chronic meth-induced degeneration.

A Novel NOX Inhibitor Alleviates Parkinson's Disease Pathology in PFF-Injected Mice.

Oxidative stress-mediated damage is often a downstream result of Parkinson's disease (PD), which is marked by sharp decline in dopaminergic neurons within the nigrostriatal regions of the brain, accounting for the symptomatic motor deficits in patients. Regulating the level of oxidative stress may present a beneficial approach in preventing PD pathology. Here, we assessed the efficacy of a nicotinamide adenine phosphate (NADPH) oxidase (NOX) inhibitor, an exogenous reactive oxygen species (ROS) regulator synthesized by Aptabio therapeutics with the specificity to NOX-1, 2 and 4. Utilizing N27 rat dopaminergic cells and C57Bl/6 mice, we confirmed that the exposures of alpha-synuclein preformed fibrils (PFF) induced protein aggregation, a hallmark in PD pathology. In vitro assessment of the novel compound revealed an increase in cell viability and decreases in cytotoxicity, ROS, and protein aggregation (Thioflavin-T stain) against PFF exposure at the optimal concentration of 10 nM. Concomitantly, the oral treatment alleviated motor-deficits in behavioral tests, such as hindlimb clasping, rotarod, pole, nesting and grooming test, via reducing protein aggregation, based on rescued dopaminergic neuronal loss. The suppression of NOX-1, 2 and 4 within the striatum and ventral midbrain regions including Substantia Nigra compacta (SNc) contributed to neuroprotective/recovery effects, making it a potential therapeutic option for PD.

Contributions of the Sodium Leak Channel NALCN to Pacemaking of Medial Ventral Tegmental Area and Substantia Nigra Dopaminergic Neurons.

We tested the role of the sodium leak channel, NALCN, in pacemaking of dopaminergic neuron (DAN) subpopulations from adult male and female mice. In situ hybridization revealed NALCN RNA in all DANs, with lower abundance in medial ventral tegmental area (VTA) relative to substantia nigra pars compacta (SNc). Despite lower relative abundance of NALCN, we found that acute pharmacological blockade of NALCN in medial VTA DANs slowed pacemaking by 49.08%. We also examined the electrophysiological properties of projection-defined VTA DAN subpopulations identified by retrograde labeling. Inhibition of NALCN reduced pacemaking in DANs projecting to medial nucleus accumbens (NAc) and others projecting to lateral NAc by 70.74% and 31.98%, respectively, suggesting that NALCN is a primary driver of pacemaking in VTA DANs. In SNc DANs, potentiating NALCN by lowering extracellular calcium concentration speeded pacemaking in wildtype but not NALCN conditional knockout mice, demonstrating functional presence of NALCN. In contrast to VTA DANs, however, pacemaking in SNc DANs was unaffected by inhibition of NALCN. Instead, we found that inhibition of NALCN increased the gain of frequency-current plots at firing frequencies slower than spontaneous firing. Similarly, inhibition of the hyperpolarization-activated cyclic nucleotide-gated (HCN) conductance increased gain but had little effect on pacemaking. Interestingly, simultaneous inhibition of NALCN and HCN resulted in significant reduction in pacemaker rate. Thus, we found NALCN makes substantial contributions to driving pacemaking in VTA DAN subpopulations. In SNc DANs, NALCN is not critical for pacemaking but inhibition of NALCN makes cells more sensitive to hyperpolarizing stimuli.SIGNIFICANCE STATEMENT Pacemaking in midbrain dopaminergic neurons (DAN) relies on multiple subthreshold conductances, including a sodium leak. Whether the sodium leak channel, NALCN, contributes to pacemaking in DANs located in the VTA and the SNc has not yet been determined. Using electrophysiology and pharmacology, we show that NALCN plays a prominent role in driving pacemaking in projection-defined VTA DAN subpopulations. By contrast, pacemaking in SNc neurons does not rely on NALCN. Instead, the presence of NALCN regulates the excitability of SNc DANs by reducing the gain of the neuron's response to inhibitory stimuli. Together, these findings will inform future efforts to obtain DAN subpopulation-specific treatments for use in neuropsychiatric disorders.

Recovery of motor function is associated with rescue of glutamate biomarkers in the striatum and motor cortex following treatment with Mucuna pruriens in a murine model of Parkinsons disease.

There is growing interest in the use of natural products for the treatment of Parkinson's disease (PD). Mucuna pruriens has been used in the treatment of humans with PD. The goal of this study was to determine if daily oral treatment with an extract of Mucuna pruriens, starting after the MPTP-induced loss of nigrostriatal dopamine in male mice, would result in recovery/restoration of motor function, tyrosine hydroxylase (TH) protein expression in the nigrostriatal pathway, or glutamate biomarkers in both the striatum and motor cortex. Following MPTP administration, resulting in an 80 % loss of striatal TH, treatment with Mucuna pruriens failed to rescue either striatal TH or the dopamine transporter back to the control levels, but there was restoration of gait/motor function. There was an MPTP-induced loss of TH-labeled neurons in the substantia nigra pars compacta and in the number of striatal dendritic spines, both of which failed to be recovered following treatment with Mucuna pruriens. This Mucuna pruriens-induced locomotor recovery following MPTP was associated with restoration of two striatal glutamate transporter proteins, GLAST (EAAT1) and EAAC1 (EAAT3), and the vesicular glutamate transporter 2 (Vglut2) within the motor cortex. Post-MPTP treatment with Mucuna pruriens, results in locomotor improvement that is associated with recovery of striatal and motor cortex glutamate transporters but is independent of nigrostriatal TH restoration.

Uncovering Novel Therapeutic Targets for Parkinson's Disease.

Parkinson's disease (PD) is the second most prevailing progressive disorder leading to neurodegeneration, typically in people above 65 years of age. Motor clinical manifestations of PD appear in a much later stage and include rigidity, tremors, akinesia, and gait dysfunction. There are also nonmotor symptoms like GI and olfactory dysfunction. However, they cannot be considered for diagnosis of the disease, as they are unspecific. PD pathogenesis is mainly characterized by deposits of inclusion bodies on dopaminergic (DA) neurons in substantia nigra pars compacta region (SNpc) of the brain. The major component of these inclusion bodies, are α-synuclein aggregates. α-Synuclein undergoes misfolding and oligomerization to form aggregates and fibrils. These aggregates gradually propagate PD pathology. Other prominent features of this pathological development include mitochondrial dysfunction, neuroinflammation, oxidative stress, and impaired autophagy. These all contribute to neuronal degeneration. Besides this, there are many underlying factors which influence these processes. These factors comprise molecular proteins and signaling cascades. In this review, we have listed out underexplored molecular targets that may aid in development of neoteric and advanced therapeutics.

Parkinson's Disease: Exploring Different Animal Model Systems.

Disease modeling in non-human subjects is an essential part of any clinical research. To gain proper understanding of the etiology and pathophysiology of any disease, experimental models are required to replicate the disease process. Due to the huge diversity in pathophysiology and prognosis in different diseases, animal modeling is customized and specific accordingly. As in other neurodegenerative diseases, Parkinson's disease is a progressive disorder coupled with varying forms of physical and mental disabilities. The pathological hallmarks of Parkinson's disease are associated with the accumulation of misfolded protein called α-synuclein as Lewy body, and degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) area affecting the patient's motor activity. Extensive research has already been conducted regarding animal modeling of Parkinson's diseases. These include animal systems with induction of Parkinson's, either pharmacologically or via genetic manipulation. In this review, we will be summarizing and discussing some of the commonly employed Parkinson's disease animal model systems and their applications and limitations.

Medial Prefrontal Cortex to Medial Septum Pathway Activation Improves Cognitive Flexibility in Rats.

BACKGROUND: The medial prefrontal cortex (mPFC) is necessary for cognitive flexibility and projects to medial septum (MS). MS activation improves strategy switching, a common measure of cognitive flexibility, likely via its ability to regulate midbrain dopamine (DA) neuron population activity. We hypothesized that the mPFC to MS pathway (mPFC-MS) may be the mechanism by which the MS regulates strategy switching and DA neuron population activity. METHODS: Male and female rats learned a complex discrimination strategy across 2 different training time points: a constant length (10 days) and a variable length that coincided with each rat meeting an acquisition-level performance threshold (males: 5.3 ± 0.3 days, females: 3.8 ± 0.3 days). We then chemogenetically activated or inhibited the mPFC-MS pathway and measured each rat's ability to inhibit the prior learned discrimination strategy and switch to a prior ignored discrimination strategy (strategy switching). RESULTS: Activation of the mPFC-MS pathway improved strategy switching after 10 days of training in both sexes. Inhibition of the pathway produced a modest improvement in strategy switching that was quantitatively and qualitatively different from pathway activation. Neither activation nor inhibition of the mPFC-MS pathway affected strategy switching following the acquisition-level performance threshold training regimen. Activation, but not inhibition, of the mPFC-MS pathway bidirectionally regulated DA neuron activity in the ventral tegmental area and substantia nigra pars compacta, similar to general MS activation. CONCLUSIONS: This study presents a potential top-down circuit from the prefrontal cortex to the midbrain by which DA activity can be manipulated to promote cognitive flexibility.

Collateral projections from the ventral tegmental area/substantia nigra pars compacta to the nucleus accumbens and insular cortex in the rat.

Midbrain dopaminergic (DAergic) regions including ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) are involved in diverse brain functions. Previous studies demonstrated that the VTA/SNc to nucleus accumbens (NAc) pathway is critical in reward and motivation. Moreover, DAergic innervations within the insular cortex (IC) are reported to play important roles in pain regulation. To investigate whether VTA/SNc sends collateral projections to NAc and IC, we injected retrograde tracer Fluoro-Gold (FG) into the NAc and Fluorescent retrograde tracer beads (RetroBeads) into the ipsilateral IC in rats. Then, to detect whether collateral projection neurons participate in neuropathic pain, parts of the rats received the spare nerve injury (SNI) surgery. The immunofluorescence staining results showed that FG, RetroBeads, and FG/RetroBeads double-labeled neurons were distributed in the VTA/SNc bilaterally with an ipsilateral predominance. The proportion of FG/RetroBeads double-labeled neurons to the total number of FG and RetroBeads-labeled neurons was 16.7% and 30.3%, respectively. About 90.3% of FG/RetroBeads double-labeled neurons showed DAergic neuron marker tyrosine hydroxylase (TH)-immunoreactive (IR), whereas, only 7.5% exhibited a subset of GABAergic inhibitory projection neuron marker parvalbumin (PV)-IR. One week after SNI, about 53.1% and 33.6% of FG- and RetroBeads-labeled neurons were FG/Fos- and RetroBeads/Fos-IR neurons, respectively. Finally, about 35.9% of the FG/RetroBeads double-labeled neurons showed Fos-IR. The present study indicates that parts of DAergic and PV-IR GABAergic neurons in the VTA/SNc send collateral projections to both NAc and IC, which are activated under SNI-induced neuropathic pain, and probably contribute to the regulation of nociception.